Transmission of HIV across mucosal surfaces is inefficient. The virus must overcome multiple structural barriers and ultimately infect metabolically active CD4+ T cells. It is well established that infection of these cells requires that the HIV envelope protein binds first to the CD4 receptor and subsequently to a co-receptor, either CCR5 or CXCR4. We have recently identified the integrin alpha4-beta7 as an additional HIV receptor on the surface of CD4+ T cells. The alpha4-beta7 receptor is the principal integrin involved in lymphocyte homing to the lamina propria of gut-associated lymphoid tissue (GALT), a site of considerable HIV replication especially during acute infection. We hypothesize that the direct interaction between HIV gp120 and alpha4-beta7 provides two advantages to HIV that allow it to transmit across mucosal surfaces in a more efficient way. By engaging alpha4-beta7, a virion is able to target an important subset of CD4+ T cells that are highly susceptible to infection. In addition, alpha4-beta7+ CD4+ T cells migrate from genital mucosa into gut lymphoid tissues where an optimal cellular environment exists for viral replication. In this way, the specific affinity of the HIV envelope for alpha4-beta7 provides plausible mechanistic explanation for the preferential establishment and/or maintenance of HIV replication in GALT. Understanding the specific molecular events surrounding mucosal transmission will hopefully allow us to identify new strategies to prevent HIV transmission.